Steroid synthesis

ABSTRACT

1. A CHEMICAL COMPOUND HAVING A CYCLOPENTANOPHENANTHRENE CARBON-CARBON SKELETON CONTAINING AT LEAST 19 AND UP TO A MAXIMUM OF 40 CARBON ATOMS AND IN WHICH AT LEAST B AND THE C RING ARE AT LEAST PARTIALLY HYDROGENATED, INCLUDING A NUCLEUS SELECTED FROM THE GROUP CONSISTING OF SATURATED AND UNSATURATED GONANE AND 8ISOGONANE NUCLEI HAVING UP TO A MAXIMUM OF FIVE (5) DOUBLE BONDS AND HAVING A PART THEREOF IN THE 13-POSITION F MONOVALENT POLYCARBON ALKYL RADICAL HAVING 2 TO ABOUT 16 CARBON ATOMS, SAID RINGS AND THE 13 AND OTHER POSITIONS OF THE NUCLEUS BEING IDENTIFIED ACCORDING TO STEROID NOMENCLATURE.

Nav. 26, 1974 G. A. HUGHES STEROID SYNTHESIS 4 Sheets-Sham 1 Filed Oct. L, 1962 N0?. 26, 1974 GA, A- HUGHES 3,850,911

sTERoIb SYNTHESIS Filedct. 4,-1962 4 Sheets-Sheet 2 12H3 :Ima 913 EHI CH2 m CH2 XSLD; CH2

o o o o o o w3 m CH2 o m54 Hm .CH50H H X CH2 o N917.` 25, 1974 G* A, HUGHES 3,850,911

STEROID SYNTHES I S Filed "OGL 4'1962 4 Sheets-Sheet .i

Hc e 5"3 @l my CH2 0H m CH2 o l OPPNAUER m130 cuo FIG? CH3 CH3 n m w20 mw20 MILD Acm HYnRoLYsls MINERAL ACID NOV. 26, 1974 G, A, HUGHES 3,850,911

STEROID SYNTHESIS Fladct. 4, 1962 4 Sheets-Sheet 4 CH3 H?, THB o l m11 CH2 0H m CH2 0H m CH2 Ol-(CHQBCHg,

m130 O o H CH 3 3 xxm cu2 0H XXXI CH2 0H @s o my; CH2 OH m CH2 o-'c'z-cng, FIG. I3

o m45 o SH2 CH2 o m CH2 o 'CH 0H OF I I *W cHo CH3() H30 m CH2 o I U.S. Cl. 260--239.5 7 Claims ABSTRACT OF THE DISCLOSURE yChemical compounds having a cyclopentanophenanthrene carbon-carbon skeleton containing at least 19 and up to a maximum of 40 carbon atoms and in which at least the B and C ring are `at least partially hydrogenated, including a nucleus selected from the group consisting of saturated and unsaturated gonane and 8-isogonane nuclel having up to a maximum of five double bonds 4and having as a part thereof in the 11i-position a monovalent polycarbon alkyl radical having 2 to about 16 carbon atoms, said rings and the 13 other positions of the nucleus -bein-g identified according to -steroid nomenclature; such compounds wherein said nucleus i-s unsaturated and has a double bond or bonds present in a position or positions selected from the following: (a) 4 position, (b) 5 position, (c) 5(10) position, (d) 2,5(10) positions, (e) 3,5 positions, (f) 1,3,5(l0) positions, (g) 1,3,5(l0.), 9(11) positions, |(h) 1,3,5(10),8 positions, or (1) 1,3,5(10),8,l4 positions; such compounds containing three (3) or more `double bonds in the nucleus and wherein the A ring 'of said nucleus is aromatic; preferably such compounds wherein the monovalent po'lycar-bon alkyl radical in ythe l3-position is ethyl; such compounds having a substituent in the 17-position linked to -s-aid 17- positi'on through a carbon-carbon bond, thus being a part of said carbon-carbon skeleton, said 17 substituent containing a maximum `of 4 carbon atoms; particularly such compounds wherein an alpha-ethynyl group is present in the 17-position; and especially such latter compounds wherein an -acetoxy or hydroxy group is also present at said l7position.

This `applic-ation is a continuation-impart of our priorfiled copending applications Ser. Nos. 57,904, filed Sept. 23, 1960; 91,341, filed Feb. 24, 1961; 137,535, filed Sept. 12, 1961; 195,000, filed May 15, 1962; and 196,557, filed May 16, 1962, all now abandoned.

This invention relates to compositions of matter classified in the art of chemistry as substituted unsaturated- -gonane derivatives, to intermediates therefor, and to processes Ifor making and using such compositions.

In describing the invention, reference will -be made in the following specification lto the annexed drawings, wherein:

FIG. 1 illustrates schematically the reaction sequence for preparing a 13-alkylgon-4-ene, specifically 13,l7a-di ethyl-'l7,8-hydroxygon-4-en-3-one.

FIG. 2 illustrates schematically the reaction sequence for preparing a 13-alkylgona-1,3,5(10)-triene from a 2- alkyl-2-(6-phenyl-3-oxohexyl) 1,3 cyclo-pentanedione, specifically 13,8-ethyl-3-methoxygona-1,3,5 (10)-trien-17- one.

FIG. 3 illustrates schematically the hydrogenation of a 13-alkylgona41,3,5(10),8,14pentaene to prepare a 13- alkyl8-isogona-l,3,5(10)-triche, specifically the converfUnited States Patent O i 3,850,911 Patented Nov. 26, 1974 ICC sion of 13-ethy1-3-methoxygona-1,3,5'(10),8,14-pentaen 17-one to 13-ethyl-3-methoxy-8-isogona-1,3,5(10)-trienl7-'one.

FIG. 4 illustrates schematically the rearrangement of a 13-alkylgona-1,3,5'(10),8-tetraene to a 13-alkylgo`nal,3, 5 10) ,9 (\1 1 tetraene, specifically 13 -ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one to 13-ethy'l-3-methoxygona-l,3,5(l0),9'(11)-tetraen-17-one.

FIG. 5 illustrates schematically the reaction sequence for preparing `a 13-alkygona-2,5(10)-diene from a 13- allrylgona-1,3,5(10),S-tetraene, specifically l3-ethyl-3- -methoxygona-LS(10)-dien-17-ol from 13ethyl3me thoxygona-1,3,5'( l0) ,8-tetraen-l7-one.

FIG. 6 illustrate-s schematically the oxidation of a 13- alkylgon'a-2,5(10)-dien-l7-ol to a 13-alkylgona-2,5(l0) dien-17-one, specifically 13,8-ethyl 3 Imetlioxygona 2, 5(10)-dien17-ol to 13,B-ethyl-S-methoxygona-Z,5(10)- dien-l7-one.

FIG. 7 illustrates schematicaly the mild hydrolysis of a 13-alkylgona-2,5(10)-diene to a 13-alkylgon-5'(10)-ene, specifically 13p ethyl 3-rnethoxygona-2,5(10)-dien-17- one to 13-ethylgon-5I(10)-en-3,17dione.

FIG. 8 illustrates schematically the mineral acid -hydrolysis of a 13-alkylgona2,5(10)-diene to a 13-alkylgon- 4-ene, `specifically 13B-ethyl 3 methoxylgona 2,5(l0) dien-17-one to l3-ethylgon-4-en-3,17-dione.

FIG. 9 illustrates schematically the reaction sequence for preparing a 13,17-dialkylgon-4-en-17-ol from a 13- alkylgona-LS(10)-dien-17-one, specifically 13,3,17a-diet'hyl-17-hydroxygon-4-en-3-one `from 3-met-hoxy-13- ethylgona2,5(10)-dien-l7-one.

FIG. 10 Iillustrates schematically. the reaction sequence for preparing a 13-alkyl-l7-alkynylgon-4-en-l7-ol from `a l3-alkylgona2,5(10)-dien-l7-one, specifically 13-ethyl- 17a-ethynyl-17-hydroxygon-4-en-3-one from l3-ethyl-3- methoxygon-2,5 10 -dien- 1 7-one.

FIG. 11 illustrates schematically the reaction sequence' for preparing an ester of a 13-alky1-l7-hydroxygon-4-ene from a 13-alkylgona-2,5(10)-dien-17-0l, specifically `the decano-ate ester of 13ethyl17-hydroxygon-4-en-3-onefrom 13-ethyl-3-methoxygona-Z'(10)-dien-17-one.

IFIG. 12 'illustrates schematically the reaction lfor preparing a mixture of a 13-alkyl n3,3 alkylenedioxygon- 5(l0)-ene and a l3-alkyl-3,3-alkylenedioxygon-5(6)-ene- `from a 13-alkyl-3-alkoxygona-2,5(10)-diene, specifically, a mixture of 13-ethyl-3,3-ethylenedioxygon-5(10)-en- 17-ol and a 1Cip-ethyl-3,3-ethylenedioxygon-5(6)-en-17- ol from 13-ethyl-3-methoxygon=a2,5-(10)-dien-17-ol.

FIG. 13 illu-strates schematically the reaction for preparing a 13-alkylgona-3,5-dien-3,17-dio1diester ironia 13- alkyl-17-hydroxygon-4-en-3-one, specifically IB-ethylgona-3,5dien-3,17-diol diacetate `from 13-ethy1-l7-hydroxygon-4-en-3-one.

FIG. 14 illustrates schematically the sequence of reactions for preparing a 13-alkyl1,3,5(10),8,14gonapentaene from a tetralone and a 1,3-cycloalkanedione having at least one hydrogen at the 2-positon, specifically 13,3-ethylgona 1,3,5(10),8,14pentaen-l7one from 'I6-f methoxy-l-tetralone and Z-ethyl-1,3-cyclopentanedionc.

The invention sought to be patented, in a principal' composition aspect, is described as residing in the concept of a chemical compound having a cyclo-aliphatic phenanthrene nucleus in which the B and the C rings are at least partially hydrogenated and having attached thereto in the 13-position a monovalent polycarbon-alkyl" radical.

The tangible embodiments of the composition aspect of the invention possess the inherent general physical properties of being white crystalline solids, are substantially insoluble in water and are generally lsoluble in polar solvents such as dimethylacetamide. Examination of compounds produced according to the hereinafter described process reveals, upon ultraviolet and infrared spectrographic analysis, spectral data supporting the molecular structures herein set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials and the mode of synthesis, confirm the structure of the compositions sought to be patented.

The tangible embodiments of the invention possess the inherent applied use characteristics of exerting qualitatively varying hormonal effects in animals as evidenced by pharmacological evaluation according to standard test procedures. Such tangible embodiments show estrogenic, androgenic, anti-estrogenic, progestational, blood lipid effects, and anabolic actions, salt retention, salt excretion and central nervous system effects. This finding indicates their usefulness in the treatment of female hypogonadism, amenorrhea, dysmenorrhea, ovulation block and contraception, functional uterine bleeding, acne, arteriosclerosis, osteoporosis, hormone dependent tumors, infertility, pregnancy maintenance, habitual abortion, weight gain and nitrogen retention, growth stimulation, post operative recovery, healing of wounds, and healing of burns. In particular it has been established that alterations of the natural steroid structure made possible by our discovery result not merely in a change of degree of hormonal activity but, as a result of the separation of types of hormonal activity, alter in an unexpected way its basic nature so that a desirable hormone effect is maximized and an undesirable hormone effect is minimized.

In addition to their inherent applied use characteristics, the intermediate compositions of this invention are useful in practicing the process aspect of the present invention in the making of the principal gonane compositions of the invention according to the sequence of reactions described herein.

The invention sought to be patented, in a principal process of making the compositions aspect, is described as residing in the concept of the sequence of reactions including: converting a compound having a S-phenylpent-l-yne nucleus, ring-unsubstituted in at least one position ortho to the point of chain attachment, by means of a Mannich type reaction, to its acetylenic amine derivative; hydrating the acetylenic linkage to form a 3-keto compound; reacting such 3-keto substrate compound with a nucleophilic 2-monovalent alkyl-1,3-dioxocyclopentano compound under Michael condensation conditions to attach the cyclopentano compound through its Z-position carbon atom to the l-position carbon atom of the 3-keto compound; treating the bicyclic triketone formed in the preceding step with an acidic dehydrating agent thereby to effect a double cyclodehydration to form a l,3,5(), 8,14-pentadehydro-l3-alkylgonane; selectively saturating the 14(15) double bond of said gonane with hydrogen in the presence of a catalyst; thereafter saturating the 8(9) double bond of the compound resulting from the preceding step; partially reducing the A-ring double bonds and the 17-carbonyl group to 17-hydroxymethylene; and, thereafter converting the so-reduced compound to a 4- dehydro-13-alkyl-17-hydroxy-gonane.

The invention sought to be patented in a second composition aspect is described as residing in the concept of a 2-(6-pheny1-3-oxohexyl)-1,3cyclopentanedione nucleus having attached thereto in the 2-position a monovalent polycarbon-alkyl radical (FIG. 1, VIII).

The tangible embodiments of said second composition aspect possess the applied use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a third composition aspect is described as residing in the concept of a.'gona-1,3,5(lO),8,14-pentaene nucleus having attached thereto in the 13position a monovalent polycarbon-alkyl radical (FIG. 1, IX).

The tangible embodiments of said third composition aspect possess the use characteristic of exerting varying hormone effects in animals as evidenced by pharmacological evaluation according to standard test procedures including estrogenic and lipid shifting effects. Furthermore, said tangible embodiments of said other secondary composition aspect possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a fourth cornposition aspect is described as residing in the concept of a gona-1,3,5 l0) ,8-tetraene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. l, X, XI, and XII).

The tangible embodiments of said fourth composition aspect possess the use characteristic of exerting varying hormone effects in animals as evidenced by pharmacological evaluation including estrogenic and lipid shifting effects. Furthermore said tangible embodiments of said fourth composition aspect possess the use characteristic of being important intermediates for the preparation o-f compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a fifth composition aspect is described in the concept of a gona-1,3,5 l0)- triene nucleus having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (FIG. 2, XIX).

The tangible embodiments of said fifth composition aspect possess the inherent applied use characteristic of exerting hormonal effects as evidenced by standard test procedures. Moreover, they are intermediates for the preparation of other compositions of the invention herein described.

The invention sought to be patented in a sixth composition aspect is described as residing in the concept of an 8- isogona-l,3,5(lO)-triene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 3, XX).

The tangible embodiments of said sixth composition aspect possess the use characteristic of exerting hormonal effects as evidenced by standard test procedures. Furthermore said tangible embodiments of said sixth composition aspect possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a seventh composition aspect is described in the concept of a gona-1,3,5- (10),9(1l)tetraene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 2, XVIII).

The tangible embodiments of said seventh composition aspect possess the inherent applied use characteristic of exerting hormonal effects as evidenced by standard test procedures. Moreover, they are intermediates which furnish a route to ll-hydroxy and ll-oxo corticoidal compounds.

The invention sought to be patented in an eighth cornposition aspect is described as residing in the concept of a gona-2,5(l0)diene nucleus having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (FIG. 5, XXIII; FIG. 6, XXXIV).

The tangible embodiments of said eighth composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore said tangible embodiments possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a ninth composition aspect is described as residing in the concept of a gon5(l0)ene nucleus having attached thereto in the l3- position a monovalent polycarbon-alkyl radical (FIG. 7, XXV).

The tangible embodiments of said ninth composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore said tangible embodiments possess the use characteristic of being important intermediates for the preparation of compositions with the use characteristic of exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a tenth composition aspect is described as residing in the concept of a `gon-Lene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 8, XXVI).

The tangible embodiments of said tenth composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore said tangible embodiments possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures,

The invention sought to be patented in an eleventh composition aspect is described as residing in the concept of a mixture of a compound having a gon-5(10)-ene nucleus and the correspondingly substituted compound having a gon5(6)ene nucleus, both of said gonenes having attached thereto in their 13-position a monovalent polycarbon-alkyl radical (FIG. 12, XXXI).

The tangible embodiments of the said eleventh composition aspect possess the use characteristic of varying hormonal effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore, said tangible embodiments of said eleventh composition aspect possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a twelfth composition aspect is described as residing in the concept of a gona-3,5-diene having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 13, XXXII).

The tangible embodiments of said twelfth composition aspect possess the use characteristic of varying hormonal effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore, said tangible embodiments of said twelfth composition aspect possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a thirteenth composition aspect is described as residing in the concept of an 8,14-secogona-l,3,5(l0),9-tetraenl4one having attached thereto in the l3-position a monovalent polycarbonalkyl radical (FIG. 14, XXXV).

The tangible embodiments of said thirteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures,

The invention sought to be patented in a fourteenth composition aspect is described as residing in the concept of a compound having a dialkylamino--phenyl-Z-hexyne nucleus (FIG. 1, IV).

The tangible embodiments of said fourteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a fifteenth composition aspect is described'as residing in the concept of a compound having a dialkylamino-6-phenyl-3-hexanone nucleus (FIG. 1, V).

The tangible embodiments of said fifteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a sixteenth composition aspect is described as residing in the concept of a compound having a 6-phenyl.-1hexen3one nucleus (FIG. 1, VI).

The tangible embodiments of said sixteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a seventeenth composition aspect is described as residing in the concept of a compound having a 2-polycarbonalkyl-l,3-cyclopentanedione nucleus (FIG. 1, VII).

The tangible embodiments of said seventeenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in an eighteenth composition aspect is described as residing in the concept of a compound having a 5,6,7,S-tetrahydro-l-phenethylindane-1,5-dione nucleus (FIG. 2, XVI).

The tangible embodiments of said eighteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity, as evidenced by standard test procedures.

The invention sought to be patented in a nineteenth composition aspect is described as residing in the concept of a hexahydro-fl-phenethylindane-1,S-dione nucleus having attached thereto in the S-position a monovalent polycarbonalkyl radical.

The tangible embodiments of said nineteenth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a sub-generic composition aspect is described as residing in the concept of a 13,17-dialkyl-l7-hydroxygon--4-en-3-one (FIG. 1, XV), of ywhich a specific embodiment, 13,17adiethyl 17hydroxygon4en3one, is hereinafter described.

The tangible embodiments of said sub-generic composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. In clinical tests, said specific embodiment has demonstrated high anabolic potency and unexpected separation of anabolic and estrogenic activities.

The invention sought to be patented in a second subgeneric composition aspect is described as residing in the concept of a 13-alkvl-17-alkynvl-17-hydroxygon4-en3 one (FIG. 10, XXVIII), of which a specific embodiment wherein the alkyl group is 13e-ethyl and the alkynyl group is 17a-ethynyl is hereinafter discussed.

The tangible embodiments of said second sub-generic composition aspect possess the use characteristic of varying hormone effects in animals, as evidenced by pharmacological evaluation by standard test procedures, and in particular have demonstrated a high progestational activity, coupled with an unexpected separation of activities.

The invention sought to be patented in a third subgeneric composition aspect is described as residing in the concept of a 17 ester of a l3-alkyl-l7-hydroxygon-4-en-3- one (FIG. 11, XXX), of which a specific embodiments in which the alkyl group is 131K-ethyl and the ester is the decanoate ester is hereinafter discussed.

The tangible embodiments of said third sub-generic composition aspect possess the use characteristic of varying hormone effects in animals, as evidenced by pharmacological evaluation by standard test procedures, and in particular in certain instances long-acting anabolic eifects accomplished by unexpected separation of activities.

The invention sought to be patented in a second process aspect is described as residing in the concept of reacting a compound having a 6-phenyl-l-hexen-3-one nucleus unsubstituted in the 1-position (FIG. 1, VI), or, alternatively, reacting a compound having a 6-phenyl-3-hexanone nucleus to which is attached at the 1position a group which will eliminate with hydrogen under Michael conditions (FIG. 1, V), with a nucleophilic compound having a 1,3-dioxocyclopentano nucleus which has at least one hydrogen in the 2-position, under Michael condensation, to attach the cyclopentano-compound nucleus through its 2-position carbon to the l-position carbon atom of the S-keto compound nucleus, thereby to form a 2-(6-phenyl- 3oxohexy1)-1,3cyclopentanedione (FIG. 1, VIII).

The invention sought to be patented in a third process aspect is described as residing in the concept of treating a compound having a 2-(6-phenyl-3-oxohexyl)-l,3cyclo pentanedione nucleus which has an ortho-para directing substituent (FIG. l, VIII), with catalytic amounts of a suitable dehydrating acid, such as polyphosphoric or ptoluene sulfonic acid, under conditions which result in the removal of water to form a tetracyclic compound (FIG. 1, IX).

The invention sought to be patented in a fourth process aspect is described as residing in the concept of selectively hydrogenating in the presence of a catalyst a compound having a gona-13,5(10),8,14-pentaene nucleus (FIG. 1, IX) and obtaining unexpectedly the corresponding compound having a 1,3,5(),8gonatetraene nucleus exclusively, with the llt-hydrogen exocyclic substituent trans to the 13-exocyclic substituent (FIG. 1, X).

The invention sought to be patented in a fifth process aspect, as illustrated in annexed FIG. 2, is described as residing in the concept of a sequence of reactions to form the gonane structure with the natural contiguration of hydrogen atoms at the 8,9 and 1ct-positions including: treating the bicyclic ketone formed in the Michael reaction of 3keto substrate compound with a nucleophilic 1,3-dioxocyclopentano compound having at least one hydrogen at the 2position (VIII) under aldol condensation conditions, i.e., in the presence of a basic catalyst, and if a suitable activating substituent is not present on the aromatic ring, in the presence of an acid catalyst, to form the tricyclic diketone (XVI): reducing the C-ring unsaturation to form Compound XVII (by whatever mechanism the hydrogen at the S-position is introduced, it can on treatment with an acid or base take up the most stable configuration, i.e., the position trans to the other newly introduced hydrogen, by equilibrating through keto-enol tautomerism with the adjacent keto; thus when the rst is a, having been introduced trans to the 13a-substituent by stereospeciic means, the 8-carbon will be so that the natural conguration results): closing the B-ring under acidic conditions at low temperature to form XVIII: and stereospecically reducing the 9,1l-unsaturation by the action of an alkali metal in liquid ammonia to also form the natural iat-hydrogen conguration at the 9-position in Compound XIX.

The invention sought to be patented in a sixth process aspect, as illustrated in annexed FIG. 3, is described as residing in the concept of catalytically hydrogenating a compound having a gona-l,3,5(10'),8,l4-pentaen-17-one nucleus (IX) in the presence of a solvent to obtain the corresponding compound having an 8isogona-l,3,5(10) trien-l7-one nucleus, i.e., a gona-1,3,5(10)-trien-l7-one in which the S-position hydrogen is in an tit-configuration instead of the -conguration of the natural gonane structure (XX). Thus, the 9,8-8,1414,l3 exocyclic substituents are in a cis-syn-trans relationship.

The invention sought to be patented in a seventh process aspect, as illustrated in annexed FIG. 4, is described as residing in the concept of a reaction comprising the rearrangement of a gona-1,3,5(10),8tetraene nucleus, having attached thereto in the 13-position a monovalent polycarbon-alkyl radical, to the corresponding gona- 1,3,5(10),9(1l)tetraene nucleus in the presence of an acid catalyst.

The invention sought to be patented in an eighth process aspect, as illustrated in annexed FIG. 5, is described as residing in the concept of sequence of reactions including: reducing a gona-1,3,5(10),8tetraen17 one nucleus, having attached thereto in the 13-position a monovalent polycarbon-alkyl radical, with an alkali metal hydride to a similarly 13-substituted gona-1,3,5(10),8 tetraen-17-ol nucleus (XXI): reducing the 8,9 double bond of XXI by alkali metal reduction in liquid ammonia to obtain a gona-1,3,5(10)-trien-17-ol nucleus (XXII) having attached thereto in the 13-position a monovalent polycarbon-alkyl radical, said nucleus having the normal gonane conguration of 9,88,1414,13 exocyclic substituents, namely, trans-anti-trans: and reducing the A- ring of Compound XXII by alkali metal reduction in liquid ammonia in the presence of a proton donor such as ethanol (Birch reduction) to obtain a compound with a gona-2,5 (10)-dien-17-o1 nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical.

The invention sought to be patented in a ninth process aspect is described as residing in the concept of a reduction of a compound with a gona1,3,5(10),8tetraen17- one nucleus, having attached" thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 5, X) under Birch reduction conditions, i.e., alkali metal in liquid ammonia in the presence of a proton donor such as methanol, to saturate the 8(9) double bond, reduce the 17-carbonyl to 17-hydroxy-methylene, and partially reduce the aromatic A-ring, obtaining a compound with a gona-2,5 (10)-diene-l7-ol having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIG. 5, XXIII) in a one-step reaction.

The invention sought to be patented in a tenth process aspect, as illustrated in annexed FIG. 6, is described as residing in the concept of an oxidation (Oppenauer) of a compound with a gona2(5(10)-diene-17-ol neculeus, having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (XXIII), to obtain a compound with a gona-2,5(10)-diene-17-one nucleus having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (XXIV).

The invention sought to be patented in an eleventh process aspect, as illustrated in annexed FIG. 7, is described as residing in the concept of a reaction comprising hydrolyzing a compound with a gona-2,5(10) diene nucleus having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (XXIV), under mild conditions, i.e., low temperature, limited time, mild acid such as oxalic, to obtain the corresponding cornpound with a gona-5(l0)en3one nucleus (XXV).

The invention sought to be patented in a twelfth process aspect, as illustrated in annexed FIG. 8, is described as residing in the concept of a reaction comprising hydrolyzing a compound with a gona-2,5 10)-diene nucleus, having attached thereto in the l3position a monovalent polycarbon-alkyl radical (XXIV), under strong conditions, i.e., heat, mineral acid, to obtain a compound with a gon-4-en-3-one nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (XXVI).

The invention sought to be patented in a thirteenth process aspect, as illustrated in annexed FIG. 9, is described as residing in the concept of a sequence of reactions including: treating a compound with 'a gona- 2,5 (10)-dien-l7-one nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (XXIV) with an alkyl Grignard reagent or metal alkyl to obtain a compound with a 17aalkylgona-2,5(l0) dien-17-o1 nucleus having attached thereto in the lli-position a monovalent polycarbon-alkyl radical (XIV), and hydrolyzing said product with mineral acid to obtain a compound with a 17a-alkyl-l7-hydroxygon-4-en-3-one nucleus having attached thereto in the 13-position a monovalent polycarbonalikyl radical (XV).

The invention sought to be patented in a fourteenth process aspect, as illustrated in annexed FIG. 10, is described as residing in the concept of a sequence of reactions including: treating a compound with a gona-2.5 ()-diene-l7-one nucleus having attached thereto in the 13position a monovalent polycarbonalkyl radical (XXIV) with an organo-metallic derivative of a l-alkyne to obtain the corresponding 17aalkynylgona2,5(10) dien-17-ol having attached thereto in the 13-position a monovalent polycarbon radical (XXVII), and hydrolyzing said product with mineral acid to obtain a 17o.- alkynyl-l7-hydroxygon-4-en-3 one having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (XXVII).

The invention sought to be patented in a fifteenth process aspect, as illustrated in annexed FIG. l1, is described as residing in the concept of a sequence of reactions including: treating a compound with a gona-2,5(10)-dien 17-ol nucleus having attached thereto in the l3-position a monovalent polycarbon-alkyl radical (XXIV) with mineral acid to obtain a compound with a 17-hydroxygon-4- en-3-one nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (XXIX), and esterifying the hydroxy group to obtain the corresponding 17-ester (XXX).

The invention sought to be patented in a sixteenth process aspect, as illustrated in annexed FIG. 14, is described as residing in the concept of a sequence of reactions including: reacting a compound having a 1tetralone nucleus (XXXIII) with a vinyl Grignard to obtain a compound with a 1vinyltetral1ol nucleus (XXXIV), condensing said tetralol with a compound with a 1,3cyclopentanedione nucleus having attached thereto in the 2-position a monovalent polycarbon-alkyl radical, to obtain a compound with a 2 [2(1,2,3,4tetrahydro1-naphthylidene) ethyl]1,3cyclopentanedione nucleus having attached to the 2position of the cyclopentane a monovalent polycarbon-alkyl radical (XXXV), cyclizing under said acid reaction conditions to obtain a compound with a gona-1,3, 5(10),8,14-pentaenl7one nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (IX).

v The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, l3,17adiethyl17hydroxygon-4-en-3-one, is illustrated. 3-(m-methoxyphenyl) propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(mmethoxyphenyl)propyl bromide (II). This halogen Compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5(mme thoxyphenyl)1pentyne (III). `Compound III is allowed to stand under .nitrogen with Water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70 C. for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)3hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(mmethoxyphenyl)1-hexe n3one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then rel0 acted with Z-ethyl 1,3 cyclopentanedione (VII) under Michael condensation conditions, eg., refluxing in methanolic potassium hydroxide to form 2-cthyl2[6(mme thoxyphenyl) -3-oxohexyl] -1,3cyclopentanedione (VIII).

Compound VIII is then cyclodehydrated at the reflux temperature of a solvent, such as benzene, in the presence of a dehydrating acid, such as p-toluene sulfonic acid, to effect simultaneous ring closures to give the tetracyclic compound 13,8-ethyl 3 methoxygona 1,3,5(10),8,l4- pentaen-l7-one (IX). The 14-unsaturation of Compound IX is then selectively hydrogenated in the presence of a metal catalyst, such as 2% palladized calcium carbonate, to form 13,6-ethyl 3 methoxygona 1,3,5(10),8 tetraen-17-one (X). Ethynylation at the 17-position of Compound X with lithium acetylide in dimethylacetamide gives 13,l7a e ethynyl 3 methoxygona 1,3,5(10),8 tetraen-17-ol (XI). The ethynyl group of Compound XI is then selectively hydrogenated to ethyl, as in the presence of a supported palladium catalyst, to produce 1319, 17a-diethyl-3-methoxygona-l,3,5(l0),8tetraen 17p ol (XII), which is then converted to 13(3,l7a-diethyl-3-methoxygona-l,3,5(10)-trien-17-ol (XIII) by alkali metal reduction in liquid ammonia, to provide the normal gonane configuration of 9,8-8,1414,13 exocyclic substituents, namely, trans-anti-trans.

By alkali metal reduction in liquid ammonia in the presence of a proton donor, such as ethanol (Birch reduction), Compound XIII is converted to 13,17adiethyl gona-2,5(10)dien17ol (XIV). By hvdrolysis in the presence of mineral acid, Compound XIV is then converted to 13,17txdiethyl 17 hydroxygon 4 en-3- one (XV).

Referring now to FIG. 2, wherein the compounds are assigned Roman numerals for identication schematically, the sequence of reactions involved in an alternate process for cyclizing the Z-aIkyl-Z-(6phenyl3oxohexyl)l,3- cyclopentanedione to obtain the tetracyclic 13alkylgona 1,3.5(10)triene is illustrated. Internal aldol condensation and dehydration of 2 ethyl-2-[6-(rnmethoxyphenyl)3 oxohexyl]-1,3-cyclopentanedione (VIII) forms 8-ethyl-5, 6.7,8-tetrahydro 4 m-methoxyphenethylindane 1,5- dione. The newly formed unsaturation of Compound VIII is hydrogenated to form 8etl1ylhexahvdro-4-m-me thoxyphenethylindane 1.5 dione (XVII). B-ring closure of Compound XVII proceeds at room temperature under acid conditions to form 13B-ethyl-S-methoxygona-l,3,5- (10),9tetraen17one (XVIII). The unsaturated bond at the 9-position is reduced with alkali metal and liquid ammonia and the product is oxidized to give 13ethylgona- 1,3,5(l0)trien17-one (XIX).

Treatment of Compound XIX with alkali metal in liquid ammonia in the presence of a proton donor reduces the A-ring to form 13ethylgona2.,5(l0) dien l7-ol (FIG. 5, XXIII). Oppenauer oxidation of XXIII gives 13-ethylgona-2,5(10)-dien-17-one l( FIG. 6, XXIV). Reaction of XXIVwith an ethyl Grignard reagent forms 138.17-diethyl 3 methoxygona-2,5(10) dien 17-ol (XIV) which is then hydrolyzed in the presence of mineral acid and is thus converted to 13,17adiethyl17 hydroxygon-4-en-3-one (XV).

The compound l3,l7adiethyl 17 hydroxygon-4- en-3-one, when administered to humans, is strongly anabolic as measured by weight gain, and shows virtually no androgenicity at therapeutic dose levels. Consistent effects on appetite stimulation are present and beneficial effects upon dermatitis and ichthyosis of mongols have been noted.

To form another specific embodiment of this invention. referring to FIG. 10, Compound XXIV, l3-ethyl3me thoxygona2,5(10)-dien-l7-one is treated with an alkali metal acetylide in liquid ammonia to convert it to 13;?- ethyl-17ot-ethynyl-3-methoxygona2,5 10) dien 17-o1 (XXVII). Compound XXVII is then converted to 13- ethyl-l7aethynyl17-hydroxygon-4-en-3one (XXVIII) When administered orally, this compound, 13 ethyll7a-ethynyl-l7-hydroxygon-4-en 3 one, demonstrates unexpectedly high progestational activity accompanied by a separation of undesirable hormone effects found in the natural steroids.

Referring to FIG. 11, a third specific embodiment of the invention, l3 ethyl 17-hydroxygon4-en3one decanoate ester k(XXX), is formed by esterication of 13 ethyl 17,6 hydroxygon-4-en-3-one (XXIX), obtained by mineral acid hydrolysis of 13 ,B ethyl-3-methoxygona 2,5() dien 17a 0l (XXIII). Compound XXIII is obtained from Compound XXIV, 13,8 ethyl- 3-methoxygona 2,5 (10) di en-17a-one, by reduction with a complex metal hydride, or alternatively from Compound X, FIG. 1, l3 ethyl 3 methoxygona-l,3,5 (10),8 tetraen 17 one, by the sequence of reactions schematically illustrated in FIG. 5, namely, complex metal hydride reduction to form 13,8 ethyl 3 methoxygona- 1,3,5(10),8 tetraen 17 ol (XXI), and then alkali metal in liquid ammonia reduction of Compound XXI to obtain l3 ethyl 3 methoxygona 1,3,5 (10)-trien- 17-o1 (XXII), followed by alkali metal in liquid ammonia reduction in the presence of a proton donor to form the before-mentioned Compound XXIII.

The compound 13,8-ethyl 17 hydroxygon-4-en-3- one decanoate ester (XXX) is a long acting anabolic agent with unexpected enhancement of anabolic activity accompanied by a decrease in androgenic activity.

While the hereinbefore described processes produce novel and steroidal-like compounds which have an unnatural substituent at the 13-position, it is apparent that the novel and valuable processes of the invention offer a unique feasible route to the corresponding natural steroids if the nucleophilic compound used in the Michael condensation step is 2-methyl-1,3-cyclopentanedione.

The aromatic ring of the phenylpropanol (FIG. l, I) used as the starting material for the preparation of the compositions and initial preparations of the invention may have one or more substituents, provided, however, at least one position ortho to the position of propanol-chain attachment is unsubstituted so that cyclodehydration to form a cyclic structure can eventually be elfectuated. To activate such ortho position for said subsequent ring closure, a para-directing group (referring to electrophilic aromatic substitution) such as hydroxy, acyloxy, alkoxy, amino, alkylamino, or acylamino is a necessary substituent on the aromatic ring. The group may be present initially or may be introduced later lbut before ring closure, either directly, or by conversion from a meta-directing group such as nitro. After the tetracyclic structure has been formed, substituents can be introduced into the aromatic A-ring which are not limited as above; however, if such substituted compound is to undergo a reduction, the group is preferably one not sensitive to reduction. After the A-ring has been reduced, the substituents on said A-ring may be the same as those originally present, or substituents to which they may be converted, such as ketonic oxygen, dialkoxy, alkylenedioxy, alkylenethioxy, and alkylenedithio; or groups introducible by known processes, such as halogen or alkyl. IFor the processes of the invention and except for the limitations expressed in this specitcation, variations of the substituents on the A-ring of the fully formed tetracyclic structures, or on the intermediates leading thereto, are full equivalents of each other.

The carbon atom to which the phenyl group of the starting propanol (I) is attached can -be substituted, as,

'for example, with an alkyl group, such as methyl or ethyl.

Moreover, this atom, to which the phenyl group is attached in Compound I, need not necessarily be carbon. It can be a hetero atom which would not interfere with subsequent catalytic reductions, as, for example, oxygen or nitrogen. This atom will appear in the tetracyclic structures of the invention in the -position, and it will be apparent, may be, as in the case of the nitrogen, substituted with hydrogen or an alkyl group.

The 2-carbon atom of the starting phenyl-propanol (I) can also be substituted, as, for example, with an alkyl group, such as methyl and ethyl, and as such, be unchanged throughout the subsequent synthesis. In the tetracyclic structures of the invention this carbon atom will appear in the 7-position.

For the processes of the invention and except for the limitations expressed in this specification, variations of the IB-ring on the fully formed tetracyclic structures, or on the intermediates leading thereto, are full equivalents of each other.

In the Michael reaction step, the 3-keto substrate cornpound can be a 6-phenyl-l-hexen-3-one, or alternatively, a 6-phenyl-3-hexanone having attached to the 1position a group which will eliminate with hydrogen to form a 6- phenyl-l-hexen-B-one under Michael conditions. Thus, a 3-keto compound with a l-dialkylamino substituent or its quaternary salt, a l-halo substituent, or a l-hydroxy substituent will react with the nucleophilic compound to form the Michael product. The nucleophilic compound can be a carbocyclic-1,3dione of varying ring size, as for example a ve-membered ring, a six-membered ring, etc., ultimately forming a corresponding inve-membered, a six-rnembered, etc., D-ring in the tetracyclic structure. The 1,3-cyclodione may also contain a hetero atom at positions other than position 2, thereby to provide av heterocyclic D-ring in the tetracyclic structure. Acylic nucleophilic compounds can be used in conducting the Michael reaction step and the open-chain of the resulting product thereafter ring-closed to form a cyclic D-ring For the processes of the invention, and except for the limitations expressed in this specification, variations of the D-ring on the fully formed tetracyclic structure, or on the intermediates leading thereto, are full equivalents of each other.

When the nucleophilic compound is 2-methyl-1,3cyclo pentanedione, the invention provides a unique total syntheseis for natural steroids: the hydrogens at the 8posi tion, 9-position, and 14-position being oc, and a respectively, as in the natural steroids. Thus such valuable therapeutic substances as estrone, estradiol, and 19-nortestosterone are made available from easily obtainable and relatively simple and inexpensive starting materials.

Moreover, by varying the group at the 2-position of the nucleophilic Michael condensation reactant, the invention provides a way to produce compounds resembling the natural steroids save at the l3-position. Thus, by varying the substituent at the 2position of the 1,3-cyclopenane`- dione, alkyl groups of varying chain length such as, for example, ethyl, isopropyl, cetyl, etc., may be introduced to form the gonane correspondingly substituted at the 13- position. Further, gonanes may be prepared wherein the l3-position is substituted with any organic radical. Thus, but without limiting the generally of the foregoing, an aralkyl, cycloalkylalkyl, or a polycar-bon-alkylene bridge bearing a hydroxy, amino, or alkylamino-substituent can readily be placed in the l3-position, and from such compounds other variations of the 13-position substituent can be prepared, as haloalkyls from hydroxyalkyls, or quaternary salts, amides, alkenyls, etc. from aminoalkyls.

For the processes of the invention and except for the limitations expressed in this specification, variations at the 13-positi0n of the fully formed tetracyclic structures or on the intermediates leading thereto are the full equivalents of the claimed l3-position polycarbon-alkyl substituents, having physiological activity of the same type.

In any of the intermediate structures or in the tetracyclic structures of the invention having either an aromatic, partially reduced, or totally reduced A-ring wherein the 17-position, or position corresponding thereto in the gonane nucleus, is carbonyl, the carbonyl group can be converted to a group such as hydroxymethylene by lithium aluminum hydride reduction; to acyloxymethylene by esterification of the hydroxymethylene group so formed; to alkoxymethylene by etherication of the hydroxymethylene group; to alkylhydroxymethylene by addition of the appropriate organometallic reagent to the carbonyl; or to alkynylhydroxymethylene b-y addition of the appropriate alkali metal acetylide in a suitable inert solvent; all in the known manners. The carbonyl group may also be ketaliized or thioketalized by treating with the appropriate alcohol or glycol in a suitable solvent under acidic conditions, as in the presence of an acid such as sulfuric acid, p-toluene sulfonic acid, or boron trifluoride etherate, with heating where necessary, according to the known art.

The specic reactions involved in the processes of the invention will now be considered, as follows, reference being made to the drawings for typifying compounds:

The vinyl ketones (VI) of the invention are prepared by elimination of dialkylamine from the corresponding dialkylaminoethyl aminoketones (V), obtained by hydration of the acetylenic linkage in an acetylenic amine (IV). The acetylenic amines (IV) can be themselves prepared by a Mannich reaction from the corresponding acetylene (III) with formaldehyde and a dialkylamine. The hydration can be carried out, for example, in aqueous sulfuric acid with mercuric sulfate as a catalyst. The corresponding quaternary salts, which may also be used in the subsequent Michael condensation, can be obtained by quaternization of the corresponding acetylenic dialkylaminoethyl amine, followed by hydration, or by quaternization of the ketoamine. The vinyl ketones can be prepared from these derivatives by the above elimination reaction. Thus the ketoamiue or its quaternary salt can be treated with a base for this purpose, for example, with sodium hydroxide or a sodium alkoxide.

The vinyl ketones (VI) and dialkylamino ketones (V) are condensed with a nucleophilic compound under Michael reaction conditions. Thus the condensation can be carried out by bringing the two reagents together in solution in the presence of a base, for example, pyridine, triethylamine, diethylamine, sodium hydroxide, or sodium methoxide, and heating as required. The nature and amount of base employed in the condensation reaction will depend upon the particular reagents used. Where the vinyl ketone derivative employed is a keto-amine and dialkylamine is eliminated in the reaction, no added base may be required. Where the compound is a 2-alkylcyclopentane-1,3dione (VII), the compound to be condensed with it is preferably a vinyl ketone, and the dione is used in excess of the molecular equivalent quantity. Suitable solvents are hydrocarbons, such as benzene, and anhydrous alcohols, such as methanol. If the reaction is carried out in benzene under rel'luxing conditions, water formed in the condensation may be azeotroped out of the reaction mixture with a Dean-Stark type trap.

As hereinbefore noted, monocyclodehydration of the C-ring is accomplished by an internal aldol condensation. The cyclodehydration can therefore be carried out using conditions generally applicable for an aldol condensation, i.e., in the presence of an acid or basic catalyst such as NaOH, p-toluene sulfonic acid, triethylamine benzoate, aluminum tertiary butoxide, and the like, either at room temperature or accompanied by heating if nec essary. In most instances, we prefer to carry out the cyclic dehydration at the boiling point of the solvent to permit azeotropic removal of the water formed during the course of the reaction, inasmuch as the aldol reaction is an equilibrium one. Preferred as solvents are the low boiling anhydrous aromatic hydrocarbons, such as benzene and Xylene. C-ring closure occurs regardless of the nat-ure of the substitution on the aromatic ring.

The reduction of the 8( 14) unsaturation in the tricyclic compounds is carried out by catalytic hydrogenation either at room temperature or above. It is found that when hydrogen and a palladium-on-charcoal catalyst are used, the hydrogen introduced at the carbon 14-position is principally in the configuration trans to the group attached at the 13-position. By whatever mechanism the hydrogen at the 8-position is introduced, it can on treatment with an acid or base take up the most stable configuration, i.e., the position trans to the other newly introduced hydrogen, by equilibrating through keto-enol tautomerism with the adjacent keto group. Thus the second hydrogen atom can be made to take up the -conguration when the first is a.

The conguration of the hydrogen atom introduced by palladium hydrogenation at the 14-carbon has been independently proved by reducing the keto group of Compound XXXVI 0 /t'w ,l

XXXVI at the 17a-position y(steroid enumeration) using sodium borohydride, a method selective for that position while leaving the other keto group untouched, and then reducing the resulting keto-alcohol (XXXVII) XXX VII with lithium in liquid ammonia, a method stereospecic for the introduction of a hydrogen at C14 trans to the angular substituent at C13 in XXXVIII,

XXXVIII followed by oxidation of the reduced keto-alcohol using chromium trioxide in an organic medium to give a crystalline diketone (XXXIX) H MGWOV whose structure was determined by reduction of the 9( l1) double bond and conversion to the known benzylidene derivative` The B-ring closure is brought about under acidic conditions. Suitable are strong acids such as sulfuric, hydrochloric, p-toluene sulfonic, etc. in solvents such as benzene, toluene, anhydrous alcohol, etc. The reaction is generally carried out at room temperature or below since heat may promote the formation of an aromatic B-ring. The preferred treatment is with methanolic hydrochloric acid at room temperature, As hereinbefore noted, it has been found that the ease of B-ring closure of the compounds of the invention to form tetracyclic compounds is affected by the nature of the substituent present on the preformed aromatic A-ring, and that subsequent cyclization is easier to carry out when the preformed aromatic A-ring contains a substituent which activates the position at Iwhich cyclization is to occur. Where a compound is to be used directly for B-ring closure, it will in practice be one containing such a substituent. Those substituents which cause subsequent B-ring closure to occur readily are substituents para to the position of ring closure which are groups that in electrophilic aromatic substitution activate an aromatic ring and are predominantly oand p-directing; for example, the hydroxy or alkoxy group.

The double cyclodehydration is brought about by dissolving a compound typified by Compound VIII in benzene containing a catalytic amount of p-toluene sulfonic acid and boiling the mixture under a Dean-Stark trap until two equivalents of water have been collected, or alternatively, by treating the same triketone with polyphosphoric acid at room temperature or slightly above until ring closure is complete.

The selective hydrogenation of the gona-8,14-dienes typified by Compound IX is carried out by means of 2% palladized calcium carbonate. As hereinbefore noted, surprisingly, the catalytic hydrogenation results in addition of hydrogen to the l4-doub1e bond in such a way as to give the natural stereochemical configuration; that is, the hydrogen adds at l4-trans to the alkyl at 13. Selective reduction of the lll-ethylenic linkage is achieved by use of catalyst, solvent combination which shows adequate selectivity, and stopping the hydrogenation when the theoretical amount of hydrogen has reacted. Solvents showing selectivity in this regard are the nonprotonic solvents, that is, hydrocarbons and ethers; benzene, toluene, naphtha, dioxan, dibutyl ether, and diethyl ether are examples of suitable nonprotonic solvents. On the other hand, protonic solvents such as acetic acid and ethanol appear to be largely non-selective.

It has been found that a moderately active Raney nickel catalyst provides good selectivity in a suitable solvent. If a Raney nickel catalyst of low activity is employed, the hydrogenation may be too slow to be useful; on the other hand, a vigorous catalyst shows poor selectivity, and some saturation of the 8,9-ethylenic bond may occur simultaneously -with the hydrogenation at the 14,15- position.

If desired, other moderately active hydrogenation catalysts may be use@ in5tead of Raney nickel; for example,

palladium on barium sulfate or on an alkaline earth metal carbonate or on charcoal have all been found suitable in this selective hydrogenation.

Saturation at the 8- or at the 9(ll)position of the tetracyclic structures must be stereospecific to obtain the natural type of exocyclic substituent configuration as noted supra. Such a sufficiently stereospeciiic reduction can be in general effected by the action of an alkali metal (sodium, potassium, or lithium) in liquid ammonia to give the normal steroid configuration hydrogen at the respective carbons. Preferably this type of reduction is carried out in the presence of a primary or secondary aromatic amine, for instance aniline, p-toluidine, or diphenylamine, as this can improve the yield of the desired product. The reduction can also be carried out in the presence of a more reactive proton donor: in this instance, the reduction of the ethylenic linkage occurs with a simultaneous reduction of the aromatic ring to give a 1,4-dihydrophenyl group.

The reduction of 9-dehydrocompounds can also be effected by catalytic hydrogenation, as this has been discovered to be sufficiently stereospecific for production of the desired trans-anti-trans compounds of normal configuration.

Catalytic hydrogenation of the gona-1,3,5(10),8,14 pentaenes, as noted above, gives a class of novel and useful 8-isomeric steroids. Solvents such as benzene, anhydrous ethanol, and methanol are suitable, and the hydrogenation is preferably carried out at room temperature and pressure.

While the tetracyclic compounds in this specification and the appended examples are named to describe the configuration correspondng to that of the natural steroids, it is to be understood that unless otherwise indicated, the product of each of the given manipulative procedures is a racemic mixture which contains said named conipound and its enantiomorph.

Representative formulations embodying specific compositions of this invention follow:

A pharmaceutical tablet for use as an oral anabolic agent consists of the following ingredients:

Mg. 13,3,17oL-diethyl-17-hydroxygon-4-en-3-one 5 Carboxymethylcellulose (viscosity 400 cps.) 15 Lactose powder 25 Redried corn starch 25 Magnesium stearate powder 4 Calcium silicate powder Q.s.

A capsule for use as an oral anabolic agent contains, in encapsulating gelatin, the following ingredients:

Mg. 1313,17a-diethyl-17-hydroxygon-4-en-3 -one 5 Finely divided silica lubricant 5 Magnesium stearate powder 5 Powdered corn starch 113 Lactose powder Qs.

An anabolic agent suspension for oral use consists of the following ingredients per 5 cc.:

An anabolic agent suspension for parenteral use consists of the following ingredients per cc.:

Mg. 13p,17a-diethyl-17-hydroxygon-4-en-3-one 0.5 Benzyl alcohol 10 Sodium chloride 90 Polyoxyethylene sorbitan monooleate 4 Sodium carboxymethylcellulose 5 Water for injection Q.s.

Pediatric drops for use as an anabolic agent consist of the following ingredients per drop (0.05 cc.):

Mg. 13,8,l7a-diethyl-17-hydroxygon-4-en-3-one 0.500 Magnesium aluminum silicate (thickening agent) 0.375 Polyoxyethylene sorbitan monolaurate 0.500 Disodium phosphate heptahydrate 0.375 Citric acid monohydrate 0.060 Glycerin 1.250 Methyl p-hydroxybenzoate 0.025 Propyl p-hydroxybenzoate 0.005 Butyl p-hydroxybenzoate 0.020 Distilled water 0.015 Sodium saccharin 0.013 Sorbitol and davor Q.s.

A long-acting anabolic agent tablet consists of the following ingredients:

13,3,l7a-diethyl-17,8-hydroxygon-4-en-3-one 5 Water-insoluble acid carboxyvinyl polymer of acrylic acid copolymerized with 0.75-2% of polyallyl sucrose (the Carbopol 934 of U.S. Pat. 2,909,-

Magnesium stearate powder 2 Lactose Q.s.

A long-acting anabolic agent suspension for parenteral use consists of the following ingredients per cc.:

Mg. 1S-ethyl-17hydroxygon4en3one l7decanoate 0.5 Benzyl alcohol l Sodium chloride 90 Polyoxyethylene sorbitan monooleate 4 Sodium carboxymethylcellulose 5 Water for injection Q.s.

A progestational agent tablet consists of the following ingredients:

Mg. l3ethyl17a-ethynyl-17-hydroxygon-4-en3-one 5 Spray dried lactose 75 Methocel (400 cps.) 12 Powdered stearic acid 6 Talc 2 Pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, avoring agents, solubilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents: it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the nely divided compound. In the tablets the compound is mixed with carrier having the necessary binding prop4 erties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to 99% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium Stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. The term preparation is intended to include the formulation of the cornpound with encapsulating material as carrier providing a capsule in which the compound (with or without other carrier) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. The compounds are insoluble in water, but can be dissolved in aqueous-organic solvent mixtures that are non-toxic in the amounts used. As an example may be mentioned water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solutions. Aqueous suspension suitable for oral use can be made by dis'- pensing the nely divided compound in water with viscous material, natural or synthetic gums, resins, etc., for example, gum arabic, ion-exchange resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents. y

Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is sub-divided in unit doses containing appropriate quantities of the compound: the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted powders of vials or ampules. The unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of compound in a unit dose of preparation may be varied or adjusted from 1 mg. to 100 mg. (generally within the range of 2.5 to 25 mg.) according to the particular application and the potency of the active ingredient.

The claimed compositions having physiological activity can be incorporated into pharmaceutical formulation including sustained-release agents.

The following preparations illustrate the manner of making the chemical compounds which are the starting materials for use in the processes of the invention.

PREPARATION 1 4,4-ethylenedioxy-4-m-nitroplnenylbutyric acid glycol monoester Add a solution of B-(m-nitrobenzoyl) propionic acid g.) (Martin, J. Amer. Chem.. Soc., 1936, 58, 1441) in benzene to toluene-psulphonic acid (50 g.) and an excess of ethylene glycol. Reux for 20 hours with removal of water in a Dean-Stark apparatus. Wash the cooled mixture with water and evaporate the solvent under reduced pressure, to obtain as a gum the crude ethylene glycol monoester of 4,4 ethylenedioxy-4-m-nitrophenylbutric acid.

PREPARATION 2 4,4-ethylenedioxy-4-m-nitrophenylbutyric acid Mix the ketal ester of Preparation 1 with an equal volume of ethanol to make it mobile, and add the solution rapidly to a relluxing solution of sodium hydroxide (50 g.) in water (200 cc.). After 3 minutes cool and pour the mixture into excess dilute acetic acid with shaking. Allow the ketal acid, 4,4-ethylenedioxy-4m-nitrophenylbutyric acid, to precipitate as a yellow granular powder and filter olf g.).

PREPARATION 3 4-maminophenyl-4,4-ethylenedioxybutyric acid Shake the nitro ketal acid of Preparation 2 (50 g.) in methanol (500 cc.) with platinum oxide catalyst (1.5 g.) in hydrogen at atmospheric pressure until hydrogenation ceases (1 hour). Remove the catalyst and evaporate the solvent under reduced pressure to obtain 4-m-aminophenyl 4,4 ethylenedioxybutyric acid as pale yellow line needles (43 g.).

PREPARATION 4 4-m-nitrophenylbutyric acid Dissolve amino ketal acid of Preparation 3 (43 g.) in liquid ammonia (l liter), add sodium (12 g.) in pieces, and stir the mixture until all the sodium dissolves and the blue color is discharged. Add ammonium chloride (19 g.) to dissolve the precipitate, and more sodium (8 g.). Cornplete removal of the ketal group is marked by a permanent blue color. Add more ammonium chloride (19 g.), evaporate and extract the solid residue with ethanol. Filter and evaporate, and then extract, lter and evaporate again to obtain crude sodium 4-m-aminophenylbutyrate. Heat on a steam bath for 6 hours at 0.05 mm. pressure to remove most of the ethylene glycol present. Shake the product for several hours in chloroform with toluene-psulphonic acid (31 g.), filter the solution, wash the residue with hot chloroform and add the hot chloroform washings to the filtrate. Evaporate the filtrate solvent to obtain crude 4-m-aminophenylbutyric acid as a gum.

Add the crude aminoacid in chloroform (75 cc.) dropwise to a hot solution of peracetic acid in apparatus fitted with a reflux condenser. When the ensuing highly exothermic reaction is complete, pour the chloroform solution into water and then remove the chloroform by steam distillation. On cooling the dark oil obtained partly solidifies. Crystallize from aqueous methanol, treating with charcoal to remove color, to obtain 4-m-nitrophenylbutyric acid, m.p. 125 C.

CH11O4N calculated: C, 57.4%; H, 5.3%. Found: C, 57.9%; H, 5.4%.

PREPARATION 5 Neutralize the nitroacid of Preparation 4 to (9 g.) in ethanol (100 cc.) with N-sodium hydroxide solution. Add a solution of silver nitrate (7.5 g.) in water cc.) with stirring, and filter, wash and dry the silver salt at 110 C.; powder the product dry at 100 C. and 0.05 mm. pressure. Suspend the dried silver salt in dry carbon tetrachloride (125 cc.) and add a solution of bromine (6 g.) in carbon tetrachloride. Reflux the mixture for 3 hours, then filter and evaporate; distill the residue to obtain 3-mnitrophenylpropyl bromide (5 g.), b.p. 140 C./0.05 mm.

PREPARATION 6 3-m -hydroxyphenylpropanl-ol An m-hydroxyphenylpropionic acid (57 g.) in dry tetrahydrofuran (250 cc.) dropwise into a vigorously stirred suspension of lithium aluminum hydride (20 g.) in tetrahydrofuran (1 liter), at a rate of addition such that gentle reuxing takes place. Reflux the mixture for 6 hours, allow to cool, and stir for 12 hours. Decompose the excess lithium aluminum hydride by careful addition of 50% aqueous ethanol (about 200 cc.), and then add l0% aqueous ethanol (about 200 cc.), and then add 10% aqueous sulphuric acid until the precipitated salts dissolve (ca. 500 cc. acid). Saturate the aqueous layer with salt while stirring, and separate the tetrahydrofuran layer. Wash the resulting aqueous layer with ether. Evaporate the tetrahydrofuran solution under reduced pressure to remove the solvent, take up the residue in ether, and add the other Washings to it. Wash the ether solution with saturated potassium bicarbonate, saturated brine, and finally dry over anhydrous magnesium sulphate. Evaporate the solvent, distill the residue under reduced pressure to obtain a liquid, b.p. 130-2/ 0.2 mm., which crystallizes on standing, forming colorless waxy crystals of 3-mhydroxyphenylpropan-l-ol (40 g.), m.p. ca. 30.

PREPARATION 7 3-m-hydroxyphenylpropylbromide Heat and stir the hydroxyphenylpropanol of Preparation 6 (10 g.) with 48% aqueous hydrogen bromide solution (5 cc.) under reiiux for 3 hours, then add a further quantity of the aqueous acid (4 cc.) and continue reuxing for 12 hours. Cool, add ether (100 cc.) and wash the ether solution with Water, aqueous potassium bicarbonate, and saturated brine. Dry the solution over anhvdrous magnesium sulphate, remove the ether and distill to obtain S-m-hydroxyphenylpropyl bromide (10 g.), b.p. 1l5-7/0.25 mm., as a colorless viscous liquid.

PREPARATION 8 Methyl 3-hydroxy-3- 3-methoxyphenyl) butanoate Add m-methoxy acetophenone g.) in benzene (450 cc.) and methyl bromoacetate (153 g.) dropwise to a mixture of acid washed activated zinc (67 g.), methyl bromoacetate (5 cc.) and a crystal of iodine in benzene (20 cc.) at such a rate that gentle refluxing takes place. After the addition is complete continue refluxing for 1 hour, cool the mixture and pour onto ice and 10% aqueous sulphuric acid. Separate the benzene layer, Wash, dry, evaporate the solvent and distill the residue to give after a forerun of reactants methyl 3-hydroxy-3-(3-methoxyphenyl)butanoate, b.p. 140, `0.65 mrn. Hg.

PREPARATION 9 Methyl 3- 3 -methoxyphenyl butanoate S-hake methyl 3-hydroxy-3-(3-methoxyphenyl)butano ate (116 g.) in acetic acid (1 l.) with 10% palladized charcoal (20 g. prehydrogenated) in an atmosphere of hydrogen until uptake of hydrogen virtually ceases (12.5 liters of hydrogen absorbed). Filter off the catalyst, evaporate the solvent and distill the residue to obtain methyl 3-(3-methoxyphenyl)butanoate, b.p. 139-142 at 5 mm. Hg M326 1.5060, 112.4 g.

Infrared absorption peak at 5 .75,u.

PREPARATION 10 3-(3-methoxyphenyl)-butan-l-ol Add methyl 3-(3-methoxyphenyl)-butanoate (112 g.) in ether (500 cc.) slowly to a stirred suspension of lithium aluminum hydride (40 g.) in ether (500 cc.). Reflux the mixture for 30 minutes, cool and decompose by adding methanol and water. Dissolve the precipitate by adding 10% sulphuric acid, separate the ether layer and extract the aqueous layer with ether. Wash the combined organic extracts with water, dry (Na2SO4), remove the solvent and distill the residue to obtain 3-(3-methoxyphenyl)butan1ol, b.p. 118-121/0.4 mm. Hg #D21 1.5260.

Ultraviolet absorption peaks at 274, 285 ma (e 1800, 1650).

Infrared absorption peaks at 3.05, 6.25,a.

PREPARATION 11 3-(3-methoxyphenyl)-n-butyl bromide Cool 3-(3-methoxyphenyl)butan-l-ol (84 g.) in benzene cc.) to 0 and add a solution of phosphorus tribromide (55 g.) in benzene (100 cc.) dropwise so that the temperature of the mixture does not rise above 5. Heat the mixture at 60 for 3 hours, cool, pour onto ice, dilute the organic layer with ether and separate it. Wash the organic solution with 3N aqueous sodium hydroxide, water and dry. Remove the solvent and distill the residue to obtain 3-(3-methoxyphenyl)-n-butyl bromide, 92.8 g., b.p. 10U-104 C./0.l5 mm.

C11H15OBr calculated: C, 54.4%; H, 6.23%; Br, 32.85%. Found: C, 54.48%; H, 6.37%; Br, 32.58%.

Infrared absorption peaks at 6.25, 12.66, 11.71n.

To prepare 3-(3 methoxyphenyl)npropyl bromide, treat 3-(3 methoxyphenyl)propan-1ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-ethoxyphenyl)-n-pentyl chloride, treat 3-(3ethoxyphenyl)pentan1-ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3 (3 methoxy-4-ethoxyphenyl)-n-propyl chloride, treat 3-(3-methoxy-4-ethoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus trichlo- 2l ride according to the manipulative procedure set forth above.

To prepare 3-(3-ethoxyphenyl)nebutyl bromide, treat 3-(3ethoxyphenyl)butan1-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3(3,S-diethoxyphenyl)-n-propyl bromide, treat 3(3,5-diethoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-propoxyphenyl)npropyl chloride, treat 3-(3-propoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3-(3-propoxyphenyl)-n-butyl bromide, treat 3-(3-propoxyphenyl)butan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-methoxy-4-propoxyphenyl)-n-propyl chloride, tre at 3- 3-methoxy-4-propoxyphenyl propan- 1- ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3-(3-methoxy-4-propoxyphenyl)-n-butyl bromide, treat 3-(3-methoxy-4-propoxyphenyl)butan1-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-pentyloxyphenyl)-npropyl bromide, treat 3-(3-pentyloxyphenyl)propan-1ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3(3cyclopentyloxyphenyl)-n-propyl chloride, treat 3-(3-cyclopentyloxypehnyl)propan-l-ol with a slight stoichimetric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3phenyln-propyl bromide, treat 3-phenylpropan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

s To prepare 3-(3,4-methylenedioxyphenyl)-n-propyl bromide, treat 3(3,4-methylenedioxyphenyl)propan-1-ol With a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3,4-dimethoxyphenyl)n-propyl bromide, treat 3-(3,4-dimethoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide accord ing to the manipulative procedure set forth above.

To prepare 2-methyl-3-(3-methoxyphenyl-npropyl bromide, treat 2 methyl3(3-methoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

PREPARATION 12 1- (m-methoxyphenyl -2-bromopropane Reflux m-methoxyphenylacetic acid (16 g.) with thionyl chloride (35 cc.) for 1 hour. Distill off the thionyl chloride at atmospheric pressure and the residue at 20 mm. pressure to give m-methoxyphenylacetyl chloride. Add dropwise simultaneously this acid chloride (l g.) in ether cc.) and a solution of sodium ethoxide (from 5 g. of the metal) in ethanol (80 cc.) to a stirred solution of diethylmalonate (18.5 g.), cooled in an ice bath at such a rate that the temperature does not rise above 5. Pour the solution slowly into dilute sulphuric acid, extract with ether, wash, dry, evaporate the solvent and reflux with a solution of sulphuric caid (48 cc.) in water (150 cc.) for 4 hours. Extract the cooled solution with ether and remove the solvent from the washed and dried solution to obtain m-methoxyphenyl acetone as an oil. Add this ketone (10 g.) in ether (5() cc.) dropwise to a stirred suspension of lithium aluminum hydride (2 g.) in ether (60 cc.) and reflux the mixture for 1 hour, then cool and decompose by carefully adding water. Dissolve the precipitate with 10% sulphuric acid and collect the product in ether. Wash, dry and evaporate the ether solution and distill the residue at 20 mm. to obtain 1(mmethoxyphenyl)propan-2-ol. Cool this alcohol (8 g.) in benzene (5 ce.) to 0 and add phosphorus tribromide (6 g.) in benzene (5 cc.) dropwise with stirring, keeping the temperature below 5 After the addition is complete, heat the mixture at 60 for 3 hours and pour the cooled solution onto ice and extract the product with ether. Wash the ethereal solution sequentially with dilute aqueous sodium hydroxide, water, dilute hydrochloric acid, and brine, and then dry. Remove the solvent and distill the residue at 20 mm. to give 1-(m-methoxyphenyl)-2-bromopropane.

PREPARATION 13 3 3 ,5-dimethoxyphenyl) -n-propyl bromide Add phosphorus tribromide (10.7 g.) in benzene (20 cc.) dropwise to 3-(3,5-dimethoxyphenyl)propan-1ol (16 g.) in benzene (25 cc.) at 0. Keep the mixture at 0 for 1 hour and then heat at 60 for 3 hours. Decompose the cooled solution by adding ice cold water. Separate the benzene layer and wash it with dilute aqueous sodium hydroxide, water, dilute hydrochloric acid and then dry. Remove the solvent and distill the residue at 20 mm. Hg to give 3-(3,5dimethoxyphenyl)-n-propyl bromide.

PREPARATION 14 5mmethoxyphenylpent l-yne Add 3-(3-methoxyphenyl)-m-propyl bromide (14 g.) in tetrahydrofuran (15 cc.) with rapid stirring to a solution of sodium acetylide (from 1.84 g. sodium) in liquid ammonia cc.) in a Dewar ilask. Continue stirring for 22 hours, then add ammonium chloride (3 g.) and water (50 cc.). Collect the product with ether and wash and dry the ethereal solution. Distill to obtain 5-m-rnethoxy-V phenylpent-l-yne (7.1 gr., 66%), b p. 75-78 C./0.06 mm. Hg.

C12H14O calculated: C, 82.7%; H, 8.1%. Found: C, 82.2%; H, 7.8%.

To prepare S-m-ethoxyphenylbept-l-yne treat 3-(3- ethoxyphenyD-m-pentyl chloride with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare S-m-propoxypent-l-yne treat 3-(3-propoxyphenyl)mpropyl chloride with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare S-m-pentyloxypent-l-yne treat 3;(3-pentyloxyphenyl)npropyl bromide with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare 5-cyclopentyloxpent-1-yne treat 3-(3-cyclopentyloxyphenyl)-n-propyl chloride with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare 5-m-propoxyhex1yne treat 3-(3-propoxyphenyD-n-butyl bromide with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare 5(3,5-diethoxy)pent1yne treat 3(3,5di ethyoxyphenyl)npropyl bromide with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare 5(3-methoxy-4-propoxy)pent-l-yne treat 3-(3-methoxy-4propoxyphenyl)-n-propyl chloride with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

To prepare 5-(3-methoxy-4-propoxy)hex-1yne treat 3-(3-methoxy-LpropoxyphenyD-m-butyl bromide with a stoichiometric excess of sodium acetylide according to the manipulative procedure set forth above.

PREPARATION 15 Sephenylpent-l-yne Add a mixture of dimethylformamide (880 cc.) and xylene (1120 cc.) to sodium acetylide (from the metal, 43.75 g.) in liquid ammonia (1250 cc.) and allow the ammonia to evaporate. Add B-phenylpropyl bromide with stirring and continue the stirring for hours while maintaining the reaction mixture at 25-30. Then add icewater (600 cc.) and extract the mixture thoroughly with ether. Dry the washed ether solution, evaporate the ether and distill the residue to give 5-phcnylpent-1-yne as an oil (121 g.), b p. 94/50 mm.

CHHIZ calculated: C, 91.6%; H, 8.4%. Found: C, 91.7%; H, 8.1%.

PREPARATION 16 5-m-nitrophenylpent-1yne Add 3-(3-nitrophenyl)npropyl bromide (5 g.) to a solution of sodium acetylide (from sodium, 0.48 g.) in liquid ammonia (100 cc.) Stir the dark solution for 12 hours, add excess ammonium chloride, evaporate the ammonia and work up the residue with ether. Distill a portion (2 g.) of the residue to obtain S-m-nitrophenylpent-1yne (1.8 g.), b.p. 130 C./0.1 mm.

Pass dry acetylene into stirred liquid ammonia (800 cc.) and add portions of sodium (totalling 10.2 g.) piece by piece as the blue color discharges. When the addition of the sodium is complete, continue to pass acetylene into the mixture for minutes. Add dimethylformamide (350 cc.) and allow the ammonia to evaporate. To the suspension of sodium acetylide thus obtained, add dropwise 3-(3- hydroxyphenyl)mpropyl bromide (33.5 g.), and heat the mixture to 60 and maintain at that temperature for 4 hours. Allow to cool, add ice and dilute sulphuric acid until the aqueous mixture is at pH 6. Extract the mixture with ether (a total of 1000 cc.) and wash the extract with saturated brine, concentrate the washed extract to 300 cc., dry over anhydrous magnesium sulphate, and evaporate off the remaining ether. Azeotrope the product with benzene to ensure no trace of water remains, to obtain as residue a dry oil, crude S-m-hydroxyphenylpent-1yne (about g.).

PREPARATION 18 Mix 5mhydroxyphenylpent1yne (about 20 g.) with pyridine (70 cc.) and acetic anhydride (30 cc.) and allow the homogeneous mixture to stand for 12 hours at room temperature. Remove excess acetic anhydride by successive additions of 95% aqueous ethanol (20 cc.) and evaporation of the ethyl acetate formed. Remove the remaining solvent and water present by adding benzene and evaporating on a water bath, to obtain a brown oil which on distillation gives 5macetoxyphenylpent1yne as a pale yellow mobile liquid (24.2 g.), b.p. 104-8/0.1 mm.

PREPARATION 19 5- (3 ,4methylenedioxyphenyl) pent- 1yne Add sodium (4.6 g.) in small pieces to a stirred solution of liquid ammonia (250 cc.) through which a rapid stream of purified acetylene is passed. When the blue color is discharged, continue the acetylene stream for 15 minutes, and then add dry dimethylformamide (120 cc.). Allow most of the ammonia to evaporate, and then add 3-(3,4 methylcnedioxyphenyl)propyl bromide (Preparation 11) g.) slowly. Stir for 3 hours at 60-70, cool the mixture in ice and decompose by the addition of water (75 cc.). Collect the product in ether and wash with 2N-sulphuric acid, ZN-sodium carbonate solution, water and dry. Remove the solvent by evaporation and distill the residue at (1).1 mm. Hg to obtain 5-(3,4-methylenedioxyphenyl) pent- -yne.

62Ilfrared (liquid lm) absorption peaks at 3.06 and To prepare 5-(3,4dimethoxyphenyl)pent-1yne treat 3-(3,4-dimethoxyphenyl)propyl bromide (25 g.) with sodium acetylide according to the manipulative procedure described above.

To prepare 5-(3,5dimethoxyphenyl)pent-1yne treat 3-(3,5-dimethoxyphenyl)propyl bromide (25 g.) with sodium acetylide according to the manipulative procedure described above.

PREPARATION 20 5-(3-methoxyphenyl)hex-1yne Add sodium (11.5 g.) slowly in small pieces to` a stirred solution of liquid ammonia (750 cc.) through which a rapid stream of acetylene is passing at such a rate that no blue color is formed. Add 3-(3methoxyphenyl)nbutyl bromide (84 g.) in tetrahydrofuran rapidly to the well stirred mixture, and after 22 hours decompose the mixture with water, collect the product with ether, wash and dry the ethereal solution and remove solvent by evaporation. Distill the residue to obtain 5-(3-methoxyplhenyD-hex-l-yne, 56.6 g., b.p. 84-95/0.55-0.35 mm.

CISHISO calculated: C, 83.00%; H, 8.57%. Found: C, 82.79%; H, 8.32%.

Infrared absorption peaks at 3.06, 4.75, 625g.

PREPARATION 21 S-(m-methoxyphenyl)-4-methyl-pent-1-yne Add l-(m-methoxyphenyl)2 bromopropane (10 g.) to a stirred suspension of magnesium (1.7 g.) in anhydrous ether (40 ce.) containing a crystal of iodine and treat the resulting Grignard solution at 0 with 2,3-dibromoprop- 1ene (9 g.) for a period of 1 hour. Reux the mixture for one hour, cool and decompose with saturated ammonium chloride solution. Wash with water and dry the ethereal phase and evaporate the solvent. Dissolve the residue (9 g.) in ether (25 cc.) and add the solution dropwise to a stirred suspension of sodamide (3.5 g.) in liquid ammonia (100 cc.) with external cooling (acetone- Dry Ice bath). Stir the mixture for 2 hours, and then allow it to warm up to room temperature. Add ether, and then add saturated aqueous ammonium chloride. Wash the ethereal solution, dry, evaporate the solution and distill the residue at 0.2 mm., the fraction boiling between and being collected, to obtain S-(m-methoxyphenyl)4methylpent1yne.

Infrared absorption peaks at 3.03 and 4.55/t.

PREPARATION 22 1-diethylamino6m-methoxyphenylhex-Z-yne Allow 5-m-methoxyphenylpent-1yne (8 g.) to stand for 12 hours at 70 C. under nitrogen with water (2.5 cc.), trioxan (0.5 g.), 30% formalin (5.5 g.), diethylamine (4. g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.13 g.). Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether; then extract the ether extract with 10% hydrochloric acid; wash the acid extract with ether, make alkaline with 10% aqueous sodium hydroxide, extract with ether, and then wash and dry the ether extract. Distill to obtain l-diethylamino-6mmethoxyphenylhex2-yne (10.6 g., 88%), b.p. 13G-131 C./0.1 mm.

C17H25N calculated: C, 78.7%; H, 9.7%. Found: C, 78.9%; H, 9.6%.

To prepare 1-diethylamino-6-m-ethoxyphenyloct-2-yne treat S-m-ethoxyphenylhept-1yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1 diethylaminoG-m-propoxyphenylhex-Z- yne treat S-m-propoxyphenylpent-1yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1 diethylamino--m-pentoxyphenylhex-2- yne treat S-m-pentoxyphenylpent-l-yne (ca. 8 g.) according to manipulative procedure described above.

To prepare 1diethylamine-6-m-cyclopentyloxyphenylhex-Z-yne treat 5mcyclopentyloxyphenylpent-1-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1 diethylamino-6-m-propoxyphenylhep-2- yne treat S-m-propoxyphenylhex-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1-diethylamino-6( 3,5-diethoxyphenyl -hex- 2-yne treat 5(3,5-diethoxyphenyl)pent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1-diethylamino-6-(3-ethoxy-4-propoxyphenyl)hex2yne treat 5-(3-ethoxy-4-propoxy)pent-l-yne (ca. i8 g.) according to the manipulative procedure described above.

To prepare 1-diethylamino-6-(3-ethoxy-4-propoxyphenyl)-hex-2-yne treat 5-(3-ethoxy-4-propoxy)-hex-l-yne (ca. 8 g.) according to the manipulative procedure described above.

PREPARATION 23 1-diethylamino-6-phenylhex-2-yne Maintain S-phenylpent-l-yne (20 g.) for 12 hours at 70 under nitrogen with `water (6.2 cc.), troxan (1.2 g.), 30% formalin (13.8 g.), diethylamine (l0 g.), acetic acid (6.9 g.), dioxan (62 cc.) and cuprous chloride (0.35 g.). Make the cooled solution alkaline with sodium hydroxide. Extract with ether and extract the ether extract itself with hydrochloric acid. Make the puried aqueous hydrochloride solution thus obtained alkaline again and extract with ether. Dry, evaporate the ether extract and distill the residue to obtain 1-diethylamino-6-phenylhex- 2-yne, (27.1 g.), b.p. 104-6 /0.2 mm.

C16H23N calculated: C, 83.8%; H, 10.1%. Found: C, 83.9%; H, 10.1%.

`Prepare l-diethylamino-6-m-nitrophenylhex-2-yne (1.5 g.), b.p. 148 C./0.05 mm., by treating S-m-nitrophenylpent-l-yne (1.8 g.) with water (0.6 cc.), trioxan (0.1 g.), 30% formalin (1.4 g.), diethylamine (1 g.), acetic acid (0.7 g.), dioxan (6.2 cc.) and cuprous chloride (0.03 g.) according to the manipulative procedure described above.

PREPARATION 24 1-diethylamino-6-m-acetoxyphenylhex-Z-yne Add S-m-acetoxyphenylpent-l-yne (9.5 g.) to a mixture of trioxan (0.5 g.), 40% formalin (5.5 g.), diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.13 g.), at room temperature. Heat the mixture thus obtained to 70, to obtain a clear green solution, and maintain under nitrogen at that temperature for 12 hours. Cool and add ice, pour the product into icecold saturated potassium bicarbonate and the extract mixture with ether. Wash and dry, evaporate the extracts under reduced pressure and distill to obtain l-diethyl amino-6-m-acetoxyphenylhex-2-yne (9.9 g.), b.p. 152-4/ 0.1 mm., as a pale yellow mobile liquid.

PREPARATION 25 1-diethylamino-6- 3,4-rnethylenedioxyphenyl -hex-2-yne All 5(3,4-methylenedioxyphenyl)pent-l-yne (24.5 g.) in dioxan (15 cc.) to a mixture of diethylamine (16 g.), troxan (7.2 g.) and cuprous chloride (0.3 g.) in dioxan cc.) and heat the mixture at 100 for 15 hours under an atmosphere of nitrogen. Filter the cooled solution, remove the solvent and distill the residue at 0.1 mm. Hg to obtain l-diethylamino--(3,4-methylenedioxyphenyl) hex-2-yne after a forerun of more volatile material.

Infrared absorption peaks at 6.25, l2.20,u..

26 PREPARATION 26 l-diethylamino-- 3,4-dimethoxyphenyl -hex-2-yne Heat a mixture of 5-(3,4dimethoxyphenyl)-pent-l-yne (8 g.), water (2.5 cc.), troxan (0.5 g.), 30% formalin (5.5 g.), diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.13 g.) at 70 for 15 hours. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and collect the product. Wash the ethereal solution with water and extract With 10% hydrochloric acid (3X 30 cc.). Wash the combined aqueous extracts with ether, make it alkaline with 10% sodium hydroxide solution and extract with ether. Wash and dry the ethereal solution, evaporate the solvent and distill the residue at 0.1 mm. Hg to obtain 1-diethylamino- 6- 3 ,4-dimethoxyphenyl -heX-2-ynef.

Infrared absorption peaks at 6.25., 12.20/u.

Prepare 1diethylamino6 (3 ,S-dimethoxyphenyl -hex- 2-yne by treating with Water, troxan, 30% formalin, diethylamine, acetic acid, dioxan and cuprous chloride according to the manipulative procedure described above.

PREPARATION 27 l-diethylamino-6-(3-methoxyphenyl)-hept-Z-yne Heat a mixture of 5-(3-methoxyphenyl)-hex-l-yne (56.6 g.), water (17.5 cc.), 40% formalin (38.5 cc.), diethylamine (40 cc.), acetic acid (19 cc.), dioxan (175 cc.) and cuprous chloride (1 g.) at 70 for 16 hours in an atmosphere of nitrogen. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract twice with ether. Wash the ether extracts with water, filter and extract with 4N hydrochloric acid (3X 350 cc.). Make the acid extracts alkaline with 10% aqueous sodium hydroxide, extract with ether and wash the organic solution with Water, brine and dry. Evaporate the solvent and distill the residue to obtain 1-diethylamino-6-(3-methoxyphenyl)hept2yne, 79.5 g., b.p. 135-40/0.2 mm. Hg. D25 1.5116.

C18H27ON calculated: C, 79.07%; H, 9.95%. Found: C, 78.99%; H, 9.67%.

PREPARATION 28 1-diethylamino-5-methyl-6- (m-methoxyphenyl hex-2-yne Heat 5-(m-methoxyphenyl)-4-methyl-pent-l-yne (8 g.) trioxan (0.5 g.) 30% formalin (5.5 cc.), diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.12 g.) together at 70 for 15 hours. Make cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and extract with 10% hydrochloric acid (3X 20 cc.). Combine the acid extracts, Wash with ether and make alkaline with 10% aque-ous sodium hydroxide and extract with ether. Wash the ethereal solution, dry, remove the solvent and distill the residue at 0.1 mm. to obtain l diethylamino5methyl6(m-methoxyphenyl)4 hex-2-yne. v

PREPARATION 29 1-chloro-6-m-methoxyphenylhexan-la-one Saturate 6-m-methoxyphenylhex-l-en-3-one (1 g.) with dry hydrogen chloride gas at 0 C. and keep the mixture at 0 C. for 48 hours. Remove the excess hydrogen chloride at 0 C. by subjecting the product to a reduced pressure of 15 mm. for 30 minutes and then at a pressure of 0.1 mm. for 15 minutes. The' product obtained shows infra-red absorption peaks at 5.87a, representing a saturated ketone group, and does not give a precipitate with aqueous-ethanolic silver nitrate solution: however, on boiling with aqueous sodium hydroxide followed by acidifcation with nitric acid and addition of silver nitrate, a copious precipitate of silver chloride is obtained. This behaviour indicates the product is the expected l-chloro-6- m-methoxyphenylhexan-3one.

27 PREPARATION 3o 1-bromo-6-m-methoxyphenylhexane-3-one Prepare 1-bromo-6mmethoxyphenylhexane3-one by saturation of 6-methoxypheny1hex-1-en-3one (g.) with dry hydrogen bromide, keeping at for 12 hours, and afterwards subjecting the product to a reduced pressure of 0.03 mm. for minutes.

The following examples illustrate the manner of using the claimed processes of the invention for the preparation of the claimed compositions of the invention, and for the preparation of natural steroids.

EXAMPLE 1 Add mercuric sulphate (0.45 g.) to a swirled solution of 1-diethylamino--m-methoxyphenylhex-2-yne (8.5 g.) in concentrated sulphuric acid (2.5 cc.) and Water (25 ce). Keep the solution unnder nitrogen at 75 C. for 1 hour, then cool, make basic with 10% aqueous sodium hydroxide, and filter through glass wool to remove mercuric oxide. Extract product with ether and wash and dry the ethereal solution. Remove the solvent to obtain the crude ketoamine 1 diethylaminc6-m-methoxyphenylhexan-3-one, infrared absorption peak at 1710u. Distill under reduced pressure with partial elimination of diethylamine, to obtain a mixture of the ketoamine l-diethylamino-6-m-methoxyphenylhexan-3-one and the vinyl ketone 6-m-methoxyphenylhex-1-en-3one (7.1 g., ca. 76% b.p. 140-145 C./0.1 mm.; infrared absorption peaks at 5.85 and 595g, the ketoamine predominating.

Distill a second portion of the crude ketoamine l-diethylamino-6mmethoxyphenylhexan3-one very slowly over a period of 30 minutes through a Vigreux fractionating column 10 cm. high and 1 in. diameter under reduced pressure to eliminate most of the diethylamine. Dissolve the 6-m-methoxyphenylhex-1-en-3-one obtained (b.p. 114-4 C./ 0.7 mm.) in ether and Wash the ether solution with dilute hydrochloric acid, followed by aqueous sodium bicarbonate and Water. Dry and evaporate. Distill the residue to give the pure vinyl ketone as a colorless liquid, b.p. 75 C./0.3 mm.

C13H16O2 calculated: C, 76.4%; H, 7.9%. Found: C, 76.3%; H, 8.0%.

Mix a third portion of the crude undistilled 1-diethyl amino-6-m-methoxyphenylhexan-3-one (3 g.) with methyl iodide (3 g.). An exothermic reaction soon develops. After 12 hours wash the mixture with ether to remove unchanged reactants and subject to reduced pressure (15 min.) to remove ether remaining: the residue is the crude methiodide of the ketoamine (4.6 g.).

Infrared absorption peaks at 5.85/r.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 2 Add to a solution of 1diethylamino-6-phenylhex-2-yne (27.1 g.) in concentrated sulphuric acid (7.6 cc.) diluted with 'Water (77 cc.) at 70 mercuric sulphate (1.6 g.), and keep the solution under nitrogen for 1 hour; cool, make basic with sodium hydroxide solution, and filter through glass Wool to remove mercuric oxide. Extract the product with ether and evaporate the washed and dried ethereal solution, leaving crude l-diethylamino--phenylhexan-3-one. Distill under reduced pressure with this ketoamine undergoing partial elimination of diethylamine, to obtain a mixture of the ketoamine, and -phenylhex-l-en- 3one (18.9 g.), b.p. 96/0.003 mm.

Infrared absorption peaks at 5.88 and 595;.

To prepare 1-diethylamino-6-m-ethoxyphenyloctan-3- one and 6-m-ethoxyphenyloct-1-en-3-one hydrate and distill 1diethylamino6-m-ethoxyphenyloct-Z-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-propoxyphenylhexan-3 one and -m-propoxyphenylhex-1-en-3-one hydrate and distill 1-diethylamino--m-propoxyphenylhex-2-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-pentoxyphenylhexan-3 one and 6mpentoxyphenylhex1-en-3-one hydrate and distill 1-diethylamino-6-m-pentoxyphenylhex-Z-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1diethylamino-6-m-cyclopentyloxyphenylhexan-3-one and 6-m-cyclopentyloxyphenylhex-1-en-3-one hydrate and distill l-diethylamino-6-m-cyclopentyloxyphenylhex-2-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino--m-propoxyphenylheptan-3 one and -m-propoxyhept-l-en-3-one hydrate and distill l-diethylamino-6-m-propoxyphenylhept-Z-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-(3,5-diethoxyphenylhexan- 3-one and 6-(3,5diethoxyphenyl)-hex-l-en-3-one hydrate and distill 1-diethylamino-6-(3,5-diethoxyphenyl)hex-2- yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare l-diethylamino 6 (3-ethoxy-4-propoxyphenyl)hexan3one and 6-(3-ethoxy-4-propoxyphenyl) hex-l-en-3-one hydrate and distill 1-diethy1amino-6-(3- ethoxy-4-propoxyphenyl)hex-Z-yne in the presence of mercury salts according to the manipulative procedure set forth above.

These compounds are useful for preparing the novel compositions of this invention which have hormonal act1v1ty.

EXAMPLE 3 1-diethylamino--m-nitrophenylhexan-3-one and 6-m-Nitrophenylhex-1-en-3-one Hydrate 1-diethylamino6-m-nitrophenylhex-2-yne (1.5 g.) using the procedure of Example 2 with one-twentieth ofthe quantities of reagents. Remove the solvent to obtam crude 1diethylamino-6-m-nitrophenylhexan3one as a clear pale yellow liquid. Distill under reduced pressure, with considerable elimination of diethylamine, to obtain crude 6-m-nitrophenylhex-1en3one (1 g.) as a clear pale yellow liquid.

EXAMPLE 4 1-diethylamino-6-m-hydroxyphenylhexan-3-one Add mercuric sulphate (0.27 g.) rapidly with swirling to a solution of 1-diethylamino-6-m-acetoxyphenylhex-2- yne (3.1 g.) in 10% aqueous sulphuric acid 15 cc.), and heat the resulting green solution at 75 under nitrogen for 11/2 hours. After cooling, filter to remove mercuric sulphate and add solid potassium bicarbonate until the product has pH 8.8. Extract the solution with ether. Wash the other extracts With brine made alkaline to pH 8.8, and dry over anhydrous magnesium sulphate. Evaporate the ether at room temperature to obtain as residue crude ldiethylamino-6-m-hydroxyphenylhexan 3 one as a viscous brown oil (2.4 g), showing infrared absorption at 5.85,u indicating the presence of a keto group, together with the characteristic band of a phenolic hydroxy group and the complete absence of a band at 5.68# corresponding to a phenolic acetate group.

This compound is useful for preparing the novel com` positions of this invention which have hormonal activity.

29 EXAMPLE `s l-diethylamino-6-m-acetoxyphenylhexan-3one and 6m-acetoxyphenylhex-1-en-3-one Acetylate the crude l-diethylamino-6-m-hydroxyphenylhexan-3-one (2.4 g.) by adding pyridine (7 cc.) and acetic anhydride (3 cc.) and allow the mixture to stand overnight at room ltemperature. Work up the mixture as in the acetylation stage described in the preparation of rnacetoxyphenylpent1yne above, to obtain crude 1-diethylamino--m-acetoxyphenylhexan 3 one as a viscous brown oil (2.7 g.).

Infrared absorption peaks at 5.68/1. with a shoulder at 5.85/i and no appreciable phenolic absorption.

Distill in a Hickman still at 0.1 mm., with partial elimination of diethylamine, and collect a colorless mobile liquid, b.p., 160-70/0.1 mm., which is a mixture (1.8 g.) of the ketoamine and -m-acetoxyphenylhex-1-en-3-one.

Infrared absorption peaks at 5.68, 5.88, 5.95,u, the nature of the absorption indicating a predominance of the vinyl ketone in the mixture.

These compounds are useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 6 Add mercuric sulphate (0.27 g.) to a swirled solution of 1 diethylamino 6 (3,4 methylenedioxyphenylhex- 2-yne) (3 g.) in 10% aqueous sulphuric acid (1'5 cc.) and heat the mixture for 90 minutes at 757 in an atmosphere of nitrogen. Filter the cooled reaction mixture and add solid potassium carbonate to pH 8.5. Extract the product 3 rwith ether, wash and dry and evaporate the sol-vent to leave as residue crude l-diethylamino-6-(3,4-hydroxyphenyl)hexane3one.

Infrared absorption peaks at 5.85/L.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 7 Add mercuric sulphate `(0.45 g.) 4to a stirred solution of 1 diethylamino 6-(3,4-dimethoxyphenyl)hex-Z-yne (8.5 g.) in concentrated sulphuric acid (2.5 cc.) and water (25 cc.) and maintain the solution at 75 for 90 minutes. r

EXAMPLE 8 1-diethylamino-6-i( 3 ,5-dimethoxyphenyl hexan-3-one and 6-(3,5-dimethoxyphenyl)hexl-en-3-one `Proceed exactly as described for the preparation of the 3,4-dimethoxy compounds above, using 6-(3,5dimethoxy phenyl)-1-diethylaminohex-2-yne (8.5 g.), mercuric sulphate (0.45 g.), and 10% sulphuric acid (25 cc.) to obtain 1 diethylamino 6 (3,5 dimethoxyphenyl)hexan3 one and 6-(3,S-dimethoxyphenylhex-l-en-3-one.

30 EXAMPLE 9 l-diethylamino-6-(m-methoxyphenyl)heptan-3-one and 6- (m-methoxyphenyl hept-1en3one `Dissolve 1 diethylamino 6 (m methoxyphenyl) hept-Z-yne A(13.6 g.) in 10% aqueous sulphuric acid (40 cc.) and stir with mercuric sulphate (0.69 g.) for 2 hours at Filter the cooled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and brine, and dry (Na2S04). Evaporate the solvent and distill the residue to obtain l-diethylamino--(m-methoxyphenyl)heptan-3- one which has partially eliminated to -6-(m-methoxyphenyl)hept1en-3one during the distillation, b.p. 145/12 mm. Hg.

Infrared absorption peaks at 5.95p.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 10 Add mercuric sulphate (0.45 g.) to a stirred ysolution of 1 diethylamino 5 methyl 6 I(m methoxyphenyl) hex-Z-yne (8 g.) in concentrated sulfuric acid (2.5 cc.) and water (25 cc.) and heat the mixture at 70 for 11/2 hrs. Filter the cooled solution, make basic with 10% aqueous sodium hydroxide extract with ether. Wash and dry the ethereal solution and evaporate to leave as residue crude 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one; infrared absorption peaks at 5.85 Slowly distill at 0.1 mm. Hg to obtain 5-methyl-6*(m-methoxyphenyl) hex-1-en-3-one; infrared absorption peaks -at 5.85/11.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 1 l 6- (m-methoxyphenyl hex- 1-en-3-one Add mercuric sulphate (1.12 g.) to a swirled solution of l-diethylamino-6-(m-methoxyphenyl)hex-Z-yne (2.5 g.) in concentrated sulphuric acid (6.25 g.) and water (62 cc.). Maintain the solution at 75 C. for 2 hours, then cool, lter, make basic and extract with ether. After the solvent has been removed, distill the residue slowly over a period of 30 minutes through a Vigreux fractionating column of height 10 om. and diameter 1 cm. under reduced pressure, to obtain the crule vinyl ketone (14.5 g., b p. 11S-23 C./0.05 mm.) containing a very small amount of ketoamine.

To obtain the pure vinyl ketone, dissolve the distillate (5.2 g.) in ether, Wash the solution with dilute hydrochloric acid, followed by water and sodium bicarbonate solution, dry, and evaporate the ether and redistill the residue. The pure vinyl ketone, 6-(m-methoxyphenyl) hex-1-en-3-one (bp. 116.8 C./0.5 mm.), shows infrared absorption peak at 5.97u.

C13H16O2 calculated: C, 76.4%; lH, 7.9%. Found: C, 76.3%, H, 8.0%. l

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE l2 l-diethylamino-6-mmethoxyphenylhexan- 3one methiodide Mix crude undistilled l-diethylamino-6-m-methoxyphenylhexan-3one (3 g.) with methyl iodide (3 g.). An exothermic reaction soon develops and after l2 hours wash the mixture with ether to remove unchanged reactants and evaporate under reduced pressure (15 mm.) to remove ether remaining; the residue is the crude methiodide of the keto-amine (4.8 g); infrared absorption peak at 1710 mit.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

311 EXAMPLE 13 2ethylcyclopentane1,3-dione Dissolve 2-ethylcyclopentane-1,3,4-trione hydrate (30 g., m.p. 65-69, Koenigs and Hopmann, Ber., 1921, 54, 1343) in ethanol (200 cc.) and water (100 cc.). To this solution add dropwise during 1 hour a solution of semicarbazide hydrochloride (21 g.) and sodium acetate (28.2 g.) in water (2010 cc.) with vigorous stirring throughout. Filter o the semicarbazone precipitated wash with methanol, and purify by stirring in reuxing methanol; filter to obtain a pale cream powder, m.p. 179- 82.

Dissolve the semicarbazone (34 g.) in a solution of potassium hydroxide (34 g.) in dry ethylene glycol at 130, and heat the mixture to 160 for 1 hour, followed by 30 minutes at 180. Distill the glycol at 0.01 mm., dissolve the residual solid in water (150 cc.) and make the solution acid to Congo red with hydrochloric acid. Cool to overnight and filter. Recrystallize the residue from water to obtain 2-ethylcyclopentane-1,3-dione (10 gn), m.p. 180 with sublimation.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 14 3-n-propylcyclopentane-1,3-dione Condense methyl n-butyl ketone with diethyl oxalate in the presence of sodium ethoxide, and convert the glyoxylate obtained by heating with hydrochloric acid to 2- nwpropylcyclopentane-1,3,5-trione, from which prepare the semicarbazone, m.p. 285-289 (decomp.) using semicarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene glycol to obtain 2npropylcyclopentane1,3-dione, m.p. 175.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 15 2isopropylcyclopentane1,3-dione Add methyl isobutyl ketone (50 g.) and diethyl oxalate (160 g.) to an ice-cold solution of sodium (23 g.) in dry ethanol (350 cc.) with efficient stirring, and then reux the mixture for 30l minutes, cool in ice and quickly add aqueous sulphuric acid (50%, 55 cc.). After l5 minutes filter off sodium sulphate, wash with ethanol and add the washings to the filtrate; next evaporate to dryness under reduced pressure to obtain ethyl 4-isopropyl-2,3,5 trioxocyclopentylglyoxalate as an uncrystallizable oil. Boil this oil with 2N hydrochloric acid (1500 cc.) for 1 hour and decant the hot solution from residual tarry material. Filter off the crystals which precipitate from the cooled decanated solution and recrystallize from aqueous ethanol as 2-isopropylcyclopentane-1,3,5-trione, m.p. 109- 112.

Treat the trione thus obtained (25 g.) by a procedure analogous to that described for the corresponding 2ethyl compound to obtain 2-isopropylcyclopenjtane-1,3-dione (8.9 g.), m.p. 146.

To p-r-epare 2-(2-hydroxyethyl)-cyc1opentane1,3dione treat 4-oxopentan-l-ol with diethyl oxalate, then subject to acid hydrolysis and treat the triene so obtained by the procedure described for the above isopropyl compound.

To prepare 2-(Z-dimethylaminopropyl)-cyclopentane- 1,3-dione treat 1-dimethylamino-hexan-S-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

To prepare 2-(2-hydroxypropy1)cyclopentanel,3dione treat 2-hydroXy-hexan-5-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

To prepare 2-phenethylcyclopentane-1,3-dione treat 1- phenylpentan-l-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

To prepare 2-isopentyl-cyclopentane-1,3-dione treat 2- methylheptan--one With diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

These compounds are useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 1G 2nbutylcyclopentane-1,3-dione Condense methyl n-pentyl ketone with diethyl oxalate in the presence of sodium ethoxide, and convert the glyoxylate obtained by heating with hydrochloric acid to 2-nbutylcyclopentane-1,3,5-trione, from which prepare the semicarbazone, m.p. 285- (decomp.) using semicarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene glycol to obtain Z-n-butylcyclopentane-1,3-dione, m.p. l49-51.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 17 2isobutyl1,3-cyclopentanedione Add methyl isoamyl ketone (228.4 g.) and diethyl oxalate (644.1 g.) to an ice-cold solution of sodium methoxide (224 g.) in dry ethanol (1400 cc.) with vigorous stirring and reflux the mixture for 11/2 hours, cool in ice water and then add aqueous sulfuric acid (202 cc. conc. sulfuric acid; 1460 cc. H2O). After reiiuxing for 11/2 hours, cool the reaction mixture containing 2-isobutylcyclopentane1,3,5trione to 25 and treat with aqueous sodium hydroxide (50%; 585 cc.). Filter off sodium sulfate precipitate and wash with methanol (800 cc.). Add the washings to the filtrate and adjust the pH of the resulting solution to 4.5 by adding glacial acetic acid (96 cc.) To this solution add dropwise and with stirring over a period of 40 minutes a solution of semicarbazide hydrochloride (223 g.) and sodium acetate (196 g.) in water (860 cc.). Filter oif the precipitate, wash with water (3 380 cc.), methanol (3 380 ml.) and dry, to obtain 3-isobutyl1,2,4 cyclopentanetrione 1 semicarbazone (184 g., 40.8% );m.p. 277.

Add the semicarbazone (184 g.) to a solution of sodium methoxide g.) in decanol (817 cc.) at 120 during 30 minutes and slowly raise the temperature to 200 to remove volatiles boiling below this temperature and then maintain between 205-215 for 3 hours. After lowering the temperature to 80, add water (820 cc.) and stir the mixture until the solids dissolve. Adjust the pH of the mixture to 8 by adding aqueous hydrochloric acid and separate the two layers. Extract the decanol layer with 2 portions (each 150 cc.) of water and wash the combined water layers with toluene. Make the aqueous solution acid to Congo red with hydrochloric acid, cool to 10, filter and dry the product, to obtain 2-isobutyl-1,3 cyclopentanedione (113.6 g., 90.6%), m.p. 194-l96 after crystallization from ethanol.

CQHMO calculated: C, 70.02%; H, 9.15%. Found: C, 70.31%; H, 9.25%.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

EXAMPLE 18 2cetylcyclopentane1,3-dione Condense methyl n-heptadecyl ketone with diethyl oxalate in the presence of sodium ethoxide to give ethyl 4- cetyl-2,3,S-trioxocyclopentyl glyoxalate, which is isolated and recrystallized from hexane, m.p. 69. `Reflux this ester with concentrated hydrochloric acid to obtain 2-cetylcyclopentane1,3,5trione monohydrate, m.p. 97-102, from 

1. A CHEMICAL COMPOUND HAVING A CYCLOPENTANOPHENANTHRENE CARBON-CARBON SKELETON CONTAINING AT LEAST 19 AND UP TO A MAXIMUM OF 40 CARBON ATOMS AND IN WHICH AT LEAST B AND THE C RING ARE AT LEAST PARTIALLY HYDROGENATED, INCLUDING A NUCLEUS SELECTED FROM THE GROUP CONSISTING OF SATURATED AND UNSATURATED GONANE AND 8ISOGONANE NUCLEI HAVING UP TO A MAXIMUM OF FIVE (5) DOUBLE BONDS AND HAVING A PART THEREOF IN THE 13-POSITION F MONOVALENT POLYCARBON ALKYL RADICAL HAVING 2 TO ABOUT 16 CARBON ATOMS, SAID RINGS AND THE 13 AND OTHER POSITIONS OF THE NUCLEUS BEING IDENTIFIED ACCORDING TO STEROID NOMENCLATURE. 